The “Forgotten” Subtypes of Breast Carcinoma: A Systematic Review of Selected Histological Variants Not Included or Not Recognized as Distinct Entities in the Current World Health Organization Classification of Breast Tumors

Breast carcinoma is the most common cancer in women. Nineteen different subtypes of breast carcinomas are recognized in the current WHO classification of breast tumors. Except for these subtypes, there are a number of carcinomas with special morphologic and immunohistochemical features that are not included in the 5th WHO classification, while others are considered special morphologic patterns of invasive breast carcinoma of no special type. In this manuscript, we systematically review the literature on four different subtypes of invasive breast carcinoma, namely lymphoepithelioma-like breast carcinoma, breast carcinoma with osteoclast-like giant cells, signet-ring breast carcinoma, and metaplastic breast carcinoma with melanocytic differentiation. We describe their clinicopathological characteristics, focusing on the differential diagnosis, treatment, and prognosis.


Introduction
Breast cancer is the most common cancer in women (accounting for 24.5% of all carcinomas).It is the leading cause of mortality (15.5%) from cancer among female patients, with a declining tendency, especially in patients of younger age (less than 50 years old) [1,2].It will affect 310,720 women and 2800 men in 2024 [3] The current World Health Organization Classification of Breast Tumors (5th edition) recognizes nineteen subtypes of invasive breast carcinoma (IBC) including IBC of no special type [4], invasive lobular carcinoma (ILC) [5,6], malignant adenomyoepithelioma [7],

Systematic Review of the Literature on Breast Carcinoma with Osteoclast-Like Giant Cel
We searched the literature for BC-OGCs on PubMed (all fields; 120 resu https://pubmed.ncbi.nlm.nih.gov,accessed on 29 March 2024), Scopus (Title/ stract/Keywords; 117 results; https://www.scopus.com/home,accessed on 29 March 20 Web of Science (all fields; 103 results; https://login.webofknowledge.com)accessed o March 2024) using the terms (("breast" OR "mammary") AND ("cancer" OR "carcinom AND ("osteoclast" AND "like" AND "giant cells")).We included all primary articles case reports in English describing BC-OGCs.Abstracts of medical conferences and pr ous reviews were excluded.Papers reporting tumors of uncertain diagnosis or stu with scant or too much aggregated data were excluded.Three authors [I.B., A.K. M.G.S.] performed the literature review and collected data.Discrepancies were correc in consensus.After applying inclusion and exclusion criteria, 43 manuscripts describ 153 cases of BC-OGCs remained for data extraction .A PRISMA flow chart w a summary of search results is shown in Figure 2.

Systematic Review of the Literature on Breast Carcinoma with Osteoclast-like Giant Cells
We searched the literature for BC-OGCs on PubMed (all fields; 120 results; https:// pubmed.ncbi.nlm.nih.gov,accessed on 29 March 2024), Scopus (Title/Abstract/Keywords; 117 results; https://www.scopus.com/home,accessed on 29 March 2024), Web of Science (all fields; 103 results; https://login.webofknowledge.com)accessed on 29 March 2024) using the terms (("breast" OR "mammary") AND ("cancer" OR "carcinoma") AND ("osteoclast" AND "like" AND "giant cells")).We included all primary articles and case reports in English describing BC-OGCs.Abstracts of medical conferences and previous reviews were excluded.Papers reporting tumors of uncertain diagnosis or studies with scant or too much aggregated data were excluded.Three authors [I.B., A.K. and M.G.S.] performed the literature review and collected data.Discrepancies were corrected in consensus.After applying inclusion and exclusion criteria, 43 manuscripts describing 153 cases of BC-OGCs remained for data extraction .A PRISMA flow chart with a summary of search results is shown in Figure 2.

Systematic Review of the Literature on Signet-Ring Cell Breast Carcinoma
We searched the literature for SRCC-B on PubMed (all fields; 433 results; https://p med.ncbi.nlm.nih.gov,accessed on 29 March 2024), Scopus (Title/Abstract/Keywords results; https://www.scopus.com/home,accessed on 29 March 2024), Web of Science fields; 423 results; https://login.webofknowledge.com,accessed on 29 March 2024 search, and the terminologies (("signet-ring") AND ("breast" OR "mammary") A ("carcinoma")).We included all primary articles and case reports in the English langu describing SRCCs, such as interventional, observational, prospective, and retrospec studies and case reports.Abstracts of medical conferences, editorials, preliminary stu with animal models, and previous reviews were excluded.Papers reporting tumor uncertain diagnosis or studies with scant or too much aggregated data were exclu Three authors [A.K., D.G. and M.G.S.] performed the literature review and collected d Discrepancies were corrected in consensus.After applying inclusion and exclusion c ria, 27 manuscripts describing 90 signet ring cell carcinoma cases remained for data traction .A PRISMA flow chart with a summary of search results is show Figure 3.

Systematic Review of the Literature on Signet-Ring Cell Breast Carcinoma
We searched the literature for SRCC-B on PubMed (all fields; 433 results; https:// pubmed.ncbi.nlm.nih.gov,accessed on 29 March 2024), Scopus (Title/Abstract/Keywords; 657 results; https://www.scopus.com/home,accessed on 29 March 2024), Web of Science (all fields; 423 results; https://login.webofknowledge.com,accessed on 29 March 2024) research, and the terminologies (("signet-ring") AND ("breast" OR "mammary") AND ("carcinoma")).We included all primary articles and case reports in the English language describing SRCCs, such as interventional, observational, prospective, and retrospective studies and case reports.Abstracts of medical conferences, editorials, preliminary studies with animal models, and previous reviews were excluded.Papers reporting tumors of uncertain diagnosis or studies with scant or too much aggregated data were excluded.Three authors [A.K., D.G. and M.G.S.] performed the literature review and collected data.Discrepancies were corrected in consensus.After applying inclusion and exclusion criteria, 27 manuscripts describing 90 signet ring cell carcinoma cases remained for data extraction .A PRISMA flow chart with a summary of search results is shown in Figure 3.

Systematic Review of the Literature on Metaplastic Breast Carcinoma with Melanocytic Differentiation
We searched the literature for MBCs with melanocytic differentiation on PubMed fields; 15 results; https://pubmed.ncbi.nlm.nih.gov,accessed on 29 March 2024), Sco (Title/Abstract/Keywords; 20 results https://www.scopus.com/home,accessed on March 2024), Web of Science (all fields; 21 results; https://login.webofknowledge.comcessed on 29 March 2024), using the terms (("breast") AND ("carcinoma") AND ("m nocytic differentiation")).We included all primary articles and case reports in English scribing metaplastic breast carcinoma with melanocytic differentiation, as well as orig articles and case reports.Abstracts of medical conferences and manuscripts repor cases in which the diagnosis was uncertain, or the studies with insufficient data were cluded.Two authors [D.D. and D.G.] performed the literature review and collected d Discrepancies were discussed and corrected in consensus.After applying inclusion exclusion criteria, six manuscripts describing seven cases of MBC with melanocytic ferentiation remained for data extraction [134][135][136][137][138][139].A PRISMA flow chart with a summ of search results is shown in Figure 4.

Systematic Review of the Literature on Metaplastic Breast Carcinoma with Melanocytic Differentiation
We searched the literature for MBCs with melanocytic differentiation on PubMed (all fields; 15 results; https://pubmed.ncbi.nlm.nih.gov,accessed on 29 March 2024), Scopus (Title/Abstract/Keywords; 20 results https://www.scopus.com/home,accessed on 29 March 2024), Web of Science (all fields; 21 results; https://login.webofknowledge.com,accessed on 29 March 2024), using the terms (("breast") AND ("carcinoma") AND ("melanocytic differentiation")).We included all primary articles and case reports in English describing metaplastic breast carcinoma with melanocytic differentiation, as well as original articles and case reports.Abstracts of medical conferences and manuscripts reporting cases in which the diagnosis was uncertain, or the studies with insufficient data were excluded.Two authors [D.D. and D.G.] performed the literature review and collected data.Discrepancies were discussed and corrected in consensus.After applying inclusion and exclusion criteria, six manuscripts describing seven cases of MBC with melanocytic differentiation remained for data extraction [134][135][136][137][138][139].A PRISMA flow chart with a summary of search results is shown in Figure 4.

Demographic and Clinicopathological Features
Lymphoepithelioma-like breast carcinoma (LELC-B) represents less than 1% breast carcinomas.It is the mammary analog of the nasopharyngeal lymphoepitheli Kumar and Kumar initially described this entity in 1994 [34].Tumors with similar phology have been described in several different organs, including the esophagus, s ach, colon, hepatobiliary tract, kidney, ureter, urinary bladder, prostate, larynx, tra lungs, major and minor salivary glands, lacrimal gland, orbital adnexa, thymus, thy uterine cervix, vagina, vulva, and skin [59].
Lymphoepitheliomas of the nasopharynx, as well as lymphoepithelioma-like c nomas (LELC) of the salivary glands, stomach, and thymus, have been associated Epstein-Barr virus (EBV) infection.In contrast, LELCs of the skin, uterine cervix, oral ity, and urinary bladder have not been related to EBV.EBV has not been detected LELC-B cases tested with various methods, including in situ hybridization [35,36,39] ymerase chain reaction [35], and immunohistochemistry [38].Three cases have been ciated with HPV infection [43,48,59].
In our review, we found 31 manuscripts describing 41 cases of LELC-B.Patien ranged from 37 to 69 years (mean 52.9 years).The mean tumor size was 24.7 mm (r
Lymphoepitheliomas of the nasopharynx, as well as lymphoepithelioma-like carcinomas (LELC) of the salivary glands, stomach, and thymus, have been associated with Epstein-Barr virus (EBV) infection.In contrast, LELCs of the skin, uterine cervix, oral cavity, and urinary bladder have not been related to EBV.EBV has not been detected in all LELC-B cases tested with various methods, including in situ hybridization [35,36,39], polymerase chain reaction [35], and immunohistochemistry [38].Three cases have been associated with HPV infection [43,48,59].
The demographic, clinical, pathological and treatment features of the reported cases are displayed in Supplementary Tables S1 and S2.
Microscopically, LELC-Bs are characterized by nests, cords, or syncytial appearance (Regaud pattern) or isolated tumor cells (Schminke pattern) associated with a dense lymphoid stroma stained positive for CD3 (T cell) and CD20 (B cell) markers.Tumor necrosis was identified in a few cases [36,41,50].Some authors have reported a lobular morphology [34,35,38,40] associated in some of these cases with lobular carcinoma in situ [34,35,38], atypical lobular hyperplasia [40], and pagetoid spread [35].None of the cases was associated with ductal carcinoma in situ.Three of the cases there were associated with sclerosing lymphocytic lobulitis [37,51,52].Glandular differentiation on electron microscopy was reported by Kurose et al. [41].The majority of LELC-Bs have a triple-negative phenotype [60].LELC-Bs mimics undifferentiated nasopharyngeal carcinoma which is associated with Epstein Barr virus (EBV); so far none of the reported cases with LELC-B are associated with EBV [60].A case of LELC-B is displayed in Figure 5.
Microscopically, LELC-Bs are characterized by nests, cords, or syncytial appearance (Regaud pattern) or isolated tumor cells (Schminke pattern) associated with a dense lymphoid stroma stained positive for CD3 (T cell) and CD20 (B cell) markers.Tumor necrosis was identified in a few cases [36,41,50].Some authors have reported a lobular morphology [34,35,38,40] associated in some of these cases with lobular carcinoma in situ [34,35,38], atypical lobular hyperplasia [40], and pagetoid spread [35].None of the cases was associated with ductal carcinoma in situ.Three of the cases there were associated with sclerosing lymphocytic lobulitis [37,51,52].Glandular differentiation on electron microscopy was reported by Kurose et al. [41].The majority of LELC-Bs have a triple-negative phenotype [60].LELC-Bs mimics undifferentiated nasopharyngeal carcinoma which is associated with Epstein Barr virus (EBV); so far none of the reported cases with LELC-B are associated with EBV [60].A case of LELC-B is displayed in Figure 5.The differential diagnosis of LELC-B includes invasive breast carcinoma with a medullary pattern (medullary carcinoma), lymphocyte-rich invasive carcinoma of ductal or lobular type, and lymphoproliferative disorders such as non-Hodgkin s and Hodgkin s lymphoma.The differential diagnosis of LELC-B includes invasive breast carcinoma with a medullary pattern (medullary carcinoma), lymphocyte-rich invasive carcinoma of ductal or lobular type, and lymphoproliferative disorders such as non-Hodgkin's and Hodgkin's lymphoma.
LELC-B is probably underrecognized because it shares histological features similar to lymphocyte-predominant breast carcinoma (LPBC).
Invasive breast carcinoma with medullary pattern is no longer recognized as a distinct entity by the current WHO classification but rather as a special morphologic pattern of IBC of NST.Histologically, it is defined as a carcinoma that fulfills a number of criteria proposed by Ridolfi et al.These criteria include complete microscopic circumscription, extensive syncytial growth pattern (more than 75%), moderate to marked lymphoid stromal infiltration, high nuclear grade and increased number of mitotic figures, lack of in situ component, or gland formation [140].Lymphocyte-rich breast carcinoma (LPBC) is a carcinoma with at least 50-60% inflammatory stroma [141].The difference between LELC-B and LPBC is the quantity of lymphocytes, which in LELC-B obscures the neoplastic cells in contrast to LPBC.Also, some architectural and cytological features may help make the correct diagnosis [36].
It could be challenging to differentiate the single-cell pattern of LELC-B from non-Hodgkin's or Hodgkin's lymphoma.In some previously reported cases, non-Hodgkin's lymphoma was the principal differential diagnosis [37,39].It is essential to know that a number of cases were initially misdiagnosed as non-Hodgkin's lymphoma [36,49,56].In these cases, immunohistochemical markers such as a panel of keratins (CKAE1/AE3, CK8/18 CK19 and CK7) together with selected lymphoid markers (CD45, CD3, CD20, CD15, CD30) may help.Positive staining for markers of epithelial differentiation paired with negative staining for lymphoid markers will provide the diagnostic solution in difficult cases.Also of note is the CD117 positivity, either diffuse or focal in few cases [49,51,57,63,64].

Molecular Studies
To the best of our knowledge there have been no studies addressing the molecular profile of these tumors.

Imaging Findings
The imaging features of BC-OGCs are not pathognomonic, showing increased peripheral vascularity at ultrasonography without any other distinguishing features [105].

Histological Findings and Differential Diagnosis
Grossly, BC-OGC presents as well-circumscribed round tumors with a characteristic dark brown or red-brown "rusty" color [68,105] On microscopic examination, the neoplastic cells may show several different histologic patterns, including tubular, cribriform, papillary, and solid; they may be arranged in a single file pattern or float in extracellular mucin.Occasionally, they may show neuroendocrine differentiation [87,94].Less frequently, tumor cells may show clear cell features [96].Importantly, the distinguishing feature of these carcinomas is the presence of large multinucleated giant cells with abundant cytoplasm and numerous centrally located nuclei expressing the histiocytic marker CD68, while there are negative for the epithelial marker CKAE1/AE3.The tumor stroma may also be infiltrated by macrophages, lymphocytes, and monocytes.Of note is the presence of extravasated red blood cells and hemosiderin deposits [104].Tumor grade was reported in 122 cases.In one case, tumor grade was unknown; 46 cases were grade I, 54 were grade II, and 21 were grade III. Figure 6 shows the histological characteristics of BC-OGC.The distinguishing histological characteristic of BC-OGC is the presence of distinct stromal features such as an inflammatory hypervascular stroma, rich in fibroblasts, with extravasated erythrocytes, monocytes, and lymphocytes together with histiocytes, and The distinguishing histological characteristic of BC-OGC is the presence of distinct stromal features such as an inflammatory hypervascular stroma, rich in fibroblasts, with extravasated erythrocytes, monocytes, and lymphocytes together with histiocytes, and multinucleated giant cells [105].The carcinoma associated with these stromal components is usually a carcinoma of no special type, but several other histotypes may be present.With this in mind, the spectrum of differential diagnoses of BCOGC may be broad.The main differential diagnosis should be made with pleomorphic carcinoma due to the presence of tumor giant cells in the latter.In contrast to osteoclast-like giant cells, which are blandlooking, pleomorphic giant cells are highly atypical, pleomorphic, and bizarre.Osteoclastlike giant cells are immunohistochemically positive for CD68 and negative for epithelial markers.The opposite is true for the giant cells of pleomorphic carcinoma.
Interestingly, in the same study transcriptomic analysis in BC-OCG along with IBC (NST) without OCG cases, revealed a separation of two gene expression profiles.BC-OCGs demonstrated significant overexpression of genes associated with OCG differentiation including TNFSF11 (encoding RANK-L that promotes osteoclast formation), TNFSFR11A (encoding RANK, the receptor of RANK-L), CSF1 (encoding the cytokine M-CSF) and CSF1R compared with IBC (NST) without OCG [102].On the other hand, the levels of OPG (encoding osteoprotegerin which suppresses RANK-L/RANK axis) were significantly lower in BC-OCG versus IBC (NST) without OCG.Immunohistochemical analysis verified gene expression profile, showing increased immunopositivity of cancer cells for RANK-L in BC-OCG [102].Interestingly, OGCs did not express RANK-L.) with a breast-conserving surgical procedure.In 2/105 (1.9%) cases the patients did not undergo surgery but instead a tru-cut [73] and a core biopsy [81] were performed respectively.

Demographic, Clinical and Pathological Features
Signet-ring cell carcinomas (SRCCs) display a signet-ring cell or signet-ring cell-like morphology that can be encountered in a variety of epithelial tumors.This morphology occurs more commonly in breast and stomach carcinomas, followed by colon, pancreas, bladder, prostate, and mesothelioma.Furthermore, several other tumors may occasionally show a signet-ring cell appearance, including mesenchymal tumors (smooth muscle tumors and ovarian stromal tumors), central nervous system tumors (oligodendrogliomas), melanomas, and lymphomas [159,160].
SRCC-B was first described in 1941 by Saphir and was classified as a distinct tumor subtype until 2003 by WHO [106].It is an extremely rare primary breast carcinoma characterized by the presence of signet-ring cell morphology in a significant proportion of tumor cells.Some previous studies have required an amount of 20% of tumor cells to have signet-ring morphology for SRCC-B diagnosis [106].Apart from SRCC-B, there is a variety of breast tumors that may display focal or diffuse signet-ring cell morphology, including invasive lobular carcinoma, lobular carcinoma in situ, invasive mucinous carcinoma, and solid papillary carcinoma.SRCC-Bs are considered highly aggressive cancers with a worse outcome than other types of breast carcinoma [106].

Imaging Findings
On mammography, SRCC-Bs may appear as an irregularly shaped [132] or lobulated [125] mass.Occasionally, no mass can be detected [116].In a recent study, around a third of cases of SRCC-Bs presented malignant calcifications [130].

Molecular Studies
To the best of our knowledge there have been no molecular studies for this rare tumor type.

Molecular Studies
To the best of our knowledge there have been no molecular studies for this rare tumor type.
A small number of cases of primary tumors with combined histological findings of carcinoma and melanoma have been described in the breast.Most authors describing these tumors consider them a rare variant of MBC.However, the latest edition of the WHO classification of breast tumors does not classify these tumors in the section on metaplastic carcinomas.It considers them a special histologic (melanotic) pattern of IBCs of NST [173].

Imaging Findings
These tumors appear as a well-circumscribed mass on mammography [134,137] and a solid hypoechoic lesion on ultrasound [137,138].

Histological Findings and Differential Diagnosis
On gross examination, tumors were well circumscribed, either solid or cystic [134], and variegated in color [134,135], tan-white [137], reddish, or brown-black [138].Connection to the overlying skin was reported only in one case [138].
Microscopically, most tumors showed an admixture of IBC of NST and melanoma features.Multidirectional differentiation was reported by Yen et al. and Noske et al., displaying glandular, squamous, melanocytic, and osseous differentiation in the first [136] and adenoid cystic carcinoma, spindle cell carcinoma and melanocytic differentiation in the second case [137].Tumors were poorly differentiated with a high mitotic index and, in some cases, with areas of necrosis.Ductal carcinoma in situ (DCIS) was present in four cases [134,135,138].
Electron microscopy showed evidence of epithelial and melanocytic differentiation and a lack of myoepithelial or neuroendocrine features [134][135][136].
Immunohistochemical study showed positive staining with markers of epithelial (CAM5.2,CKAE1/AE3, EMA) and melanocytic (HMB-45, Melan-A) differentiation in the areas showing morphological features of carcinoma and melanoma, respectively.Interestingly, it has been shown S-100 immunopositivity both by the two components [135].CD117 was positive in the case with adenoid cystic carcinoma component [137].One case showed focal positive HMB-45 staining in the DCIS [134].Estrogen and progesterone receptors and HER-2 were negative in all cases.
The differential diagnosis of MBC with melanocytic differentiation includes collision tumors, cancer-to-cancer metastasis, and carcinoma with melanin pigmentation.Histologically, the presence of DCIS, evidence of morphologic transition, and multidirectional differentiation are against the possibility of a collision tumor or cancer-to-cancer metastasis.Furthermore, immunohistochemical staining of the pigmented cells for HMB-45 is a clue of true melanocytic differentiation.

Molecular Studies
To address the clonal relationship between the carcinoma and melanoma components Bunsei et al. [135] performed polymerase chain reaction (PCR)-based microsatellite analysis and found the same patterns of loss of heterozygosity (LOH) in the carcinoma and melanoma components in the primary and metastatic site as well as in situ carcinoma.These findings suggest that both tumor components share the same clonal origin.Be-sides, this evidence support that breast carcinoma diverged to melanoma early during carcinogenesis in premalignant lesion.

Outcome
Follow-up was reported in 4/7 (57.1%) [134,135,138] cases ranging from 12 to 72 months (median 14).During this period, two of the patients were alive without evidence of disease [134,138], one was alive with disease [134], and one died of disease [135].

Survival
We performed survival analysis for the patients of the four entities (see Figure 8), according to the results, there is statistically significant difference in the survival of the patients (p = 0.028).Post hoc analysis showed that (a) patients with LELC had better survival than patients with MBCMD (p = 0.0027) (b) patients with LELC had no difference in survival compared to patients with BCOGC (p = 1) (c) patients with LELC had better survival from patients with SRCC (p = 0.009) (d) patients with MBCMD had worst survival from patients with BCOGC (p = 0.0027) but (e) no difference was confirmed when compared to patients with SRCC and finally (f) a marginal significance (p = 0.091) was detected when comparing patients with BCOGC with those having SRCC the latter having worst survival probability.Considering survival of patients with LELC and BCOGC, since there was not available monitoring time data we compared the survival percentage, for LELC was 100% and for BCOGC it was 90.7% which leads to statistically confirmed difference (p = 0.021).

Clinicopathological Features of the Four Entities
Cumulative results of all entities are presented in Table 1.Differences among the four entities were present for several characteristics, among them patient age, tumor size, treatment approach and as evident from the previous paragraph, survival (see Table 1 for details).

Clinicopathological Features of the Four Entities
Cumulative results of all entities are presented in Table 1.Differences among the four entities were present for several characteristics, among them patient age, tumor size, treatment approach and as evident from the previous paragraph, survival (see Table 1 for details).

Figure 1 .
Figure 1.PRISMA 2020 flowchart showing the search strategy, excluded studies, and finally cluded reports of lymphoepithelioma-like breast carcinomas.

Figure 1 .
Figure 1.PRISMA 2020 flowchart showing the search strategy, excluded studies, and finally included reports of lymphoepithelioma-like breast carcinomas.

Figure 2 .
Figure 2. PRISMA 2020 flowchart showing the search strategy, excluded studies, and finall cluded reports of breast carcinomas with osteoclast like giant cells.

Figure 2 .
Figure 2. PRISMA 2020 flowchart showing the search strategy, excluded studies, and finally included reports of breast carcinomas with osteoclast like giant cells.

Figure 3 .
Figure 3. PRISMA 2020 flowchart showing the search strategy, excluded studies, and finally cluded reports of signet-ring cell breast carcinomas.

Figure 3 .
Figure 3. PRISMA 2020 flowchart showing the search strategy, excluded studies, and finally included reports of signet-ring cell breast carcinomas.

Figure 4 .
Figure 4. PRISMA 2020 flowchart showing the search strategy, excluded studies, and final cluded reports of metaplastic carcinomas with melanocytic differentiation.

Figure 4 .
Figure 4. PRISMA 2020 flowchart showing the search strategy, excluded studies, and finally included reports of metaplastic carcinomas with melanocytic differentiation.

Figure 6 .
Figure 6.(A) On low power examination, malignant epithelial cells are lying close to large multinucleated giant cells with abundant cytoplasm and numerous centrally located nuclei (Hematoxylin and

Figure 7 .
Figure 7. (A) On medium power examination, tumor cells show a pure signet ring cell morphology with displacement of the cell nucleus (Hematoxylin and Eosin, H&E; ×200); (B) On immunohistochemical examination positive immunostaining for E-cadherin reveals the ductal nature of the carcinoma (E-cadherin mouse monoclonal NCH-38, Dako ×200) (original, previously unpublished photos).

Figure 7 .
Figure 7. (A) On medium power examination, tumor cells show a pure signet ring cell morphology with displacement of the cell nucleus (Hematoxylin and Eosin, H&E; ×200); (B) On immunohistochemical examination positive immunostaining for E-cadherin reveals the ductal nature of the carcinoma (E-cadherin mouse monoclonal NCH-38, Dako ×200) (original, previously unpublished photos).

Table 1 .
Summary table of the main clinicopathological features of the four entities.